Substitute 1-(piperidin-4-yl)-3-(aryl)-isothioureas, their preparation and therapeutic use

ABSTRACT

The invention concerns compounds of formula (I) wherein: R1 and R2, identical or different, represent a saturated or unsaturated alkyl radical, branched or not and containing 1 to 7 carbon atoms; R3 to R8, identical or different, represent a hydrogen, an alkyl branched or not and containing 1 to 5 carbon atoms, an acyloxy, branched or not and containing 1 to 5 carbon atoms, a halogeno, nitro, hydroxy, acyl or alkoxy group containing 1 to 5 carbon atoms, a dialkylamino group containing 1 to 5 carbon atoms, a trifluoromethyl or trifluoro methoxyl group; Z represents an oxygen or sulphur atom or methylene; m represents an integer between 0 and 4 inclusively; n represents an integer between 2 and 7 inclusively; and their pure enantiomers and mixtures, the therapeutically acceptable mineral or organic salts of the compounds of formula (I) and their possible hydrates.

The invention relates to novel substituted1,2-dialkyl-1-[1-[aryl(alkyl)oxyalkyl]piperidin-4-yl]-3-arylisothioureas,to their process of preparation and to their use as medicament.

A previous patent of the Applicant Company (WO-97/05134) claimedN-alkyl-N-[1-((ω-aryloxyalkyl)piperidin-4-yl]-4H-3,1-benzothiazin-2-aminederivatives having therapeutic interest, particularly in the treatmentof myocardial ischemia.

In order to bring about greater flexibility in the active molecule,capable of increasing its bioavailability and its solubility, the “open”compounds of the preceding series of benzothiazines were synthesized andallowed a novel class of compounds to be identified which is asubject-matter of the present invention: substituted3-aryl-1-(piperidin-4-yl)-1-alkylisothioureas. Their pharmacologicalstudy has generally shown an activity greater than that of the cyclicseries based on the in vitro test of contraction with veratrine of therat isolated left atrium and in the ischemia test on the perfusedisolated heart of the guinea pig.

Claimed Molecules

The molecules of the present invention belong to the class of the N- andS-substituted 1-(1-aryl(alkyl)oxyalkylpiperidin-4-yl)-3-arylisothioureasof formula I:

in which:

R₁ and R₂, which are identical or different, represent a saturated orunsaturated and branched or unbranched alkyl radical having from 1 to 7carbon atoms,

R₃ to R₈, which are identical or different, represent:

a hydrogen,

a branched or unbranched alkyl having from 1 to 5 carbon atoms,

a branched or unbranched alkyloxy having from 1 to 5 carbon atoms,

a halo group,

a nitro group,

a hydroxyl group,

an acyl or acyloxy group having from 2 to 5 carbon atoms,

a dialkylamino group having from 1 to 5 carbon atoms,

a trifluoromethyl or trifluoromethoxyl group,

Z represents an oxygen or sulfur atom or a methylene,

m represents an integer varying from 0 to 4 inclusive,

n represents an integer between 2 and 7 inclusive.

The invention relates just as well, when they exist, to the pure R or Sisomers or their mixtures.

The present invention includes the therapeutically acceptable inorganicor organic salts of the compounds of formula I and their possiblehydrates.

The invention also relates to the process for the preparation of theclaimed compounds and to their application as medicaments.

The molecules of the present invention possess noteworthy cytoprotectiveproperties superior to those of the cyclic series of the family of the4H-3,1-benzothiazin-2-amines and of the reference products, such asR56865.

Synthesis of the Compounds of Formula I

The1,2-dialkyl-1-[1-[aryl(alkyl)oxyalkyl]piperidin-4-yl]-3-arylisothioureas(I) are prepared in two stages from theN-alkyl-N-[1-(aryl)oxyalkyl-piperidin-4-yl]amines (II). The condensationof these amines (II) with an aryl isothiocyanate (III) according to themethod of Kaye and Parris (J. Org. Chem., 1951, 16, 1859-1863) providesthe corresponding thiourea (IV).

The S-alkylation of the latter is carried out by condensation of ahaloalkane or of a dialkyl sulfate, either by adapting the method ofDupin S. and Pesson M. (Bull. Soc. Chim. Fr., 1963, 144-150) or by usingcalcium oxide to block the iodides formed by extrapolating the method ofHonkenen. E. et al. (J. Med. Chem., 1983, 26, 1433-38), to give directlythe compound I of the present invention (cf. Scheme 1).

In the case where m=0 (Scheme 2), the intermediate amines (II) wereprepared according to Ismaiel A. M. (J. Med. Chem., 1993, 36, 2519-2525)as described above in Patent WO 97/05134, using sodiumtriacetoxyborohydride as reducing agent in the final stage according toAbdel-Magid A. F. et al. (J. Org. Chem., 1996, 61, 3849-3862).

If m≠0, the etherification reaction (first stage, Scheme 2) can becarried out starting from the corresponding alcohol with 50% sodiumhydroxide solution by PTC according to Burgstahler et al., J. Org.Chem., 1977, 42, 566-8.

The phenyl isothiocyanates which are not available commercially areprepared from the corresponding anilines by usingthiocarbonyldiimidazole as described by Staab H. A. and Walther G.(Liebigs Ann. Chem., 1962, 567, 104-[lacuna]).

EXAMPLE 11,2-Dimethyl-3-phenyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]isothioureahydrogen fumarate (1)

1.1)

1-Methyl-3-phenyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]thiourea(1.1)

A mixture formed of 2 g (14.8 mmol) of phenyl isothiocyanate, 5.5 g(14.8 mmol) ofN-methyl-1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-ylaminedihydrochloride (cf. WO 97/05134) and 4.1 ml (29.6 mmol) oftriethylamine in 25 ml ethanol is brought to reflux for 2 h. Afterreturning to 25° C., the mixture is evaporated to dryness and theresidue is taken up in 30 ml of water and extracted with methylenechloride. The organic phase is washed with water and with aqueous salinesolution and then dried over anhydrous sodium sulfate. After removingthe insoluble inorganic material, the filtrate is evaporated to drynessto give a cream solid (m=5.9 g) which, triturated in isopropyl alcohol,gives 5.3 g (Yd: 83%) of off-white powder of formula 1.1.

Empirical formula: C₂₃H₂₉F₂N₃OS

Molecular mass: 433.54

Melting point: 152-3° C.

NMR (d₆-DMSO) δ: 1.4-1.85 (m, 8H), 1.93 (m, 2H), 2.33 (m, 2H), 2.95 (m,2H), 3.03 (s, 3H), 3.98 (t, 2H), 5.04 (m, 1H), 6.7-6.9 (m, 1H), 7.02-7.2(m, 2H), 7.25-7.4 (m, 5H), 9 (s, 1H).

1.2)1,2-Dimethyl-3-phenyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]isothioureahydrogen fumarate (1)

A solution of 2 g (4.6 mmol) of the preceding urea (1.1) in a mixture of30 ml of dichloromethane and 40 ml of ethanol is treated in a 100 mlround-bottomed flask with 302 μl (0.69 g or 4.84 mmol) of methyl iodideand stirred overnight at 25° C. The mixture is evaporated to dryness istaken up in dichloromethane and water. The organic phase is separated,washed with aqueous saline solution and dried over anhydrous sodiumsulfate. The insoluble inorganic material is filtered off and thefiltrate is evaporated to dryness: yellow oil (2 g). This oil ispurified by flash chromatography, elution being carried out with a97.5/2.25/0.25 CH₂Cl₂/CH₃OH/NH₄OH mixture. The fractions having theexpected thiourea are evaporated: light yellow oil (m=2.1 g; Yd: 66%).

Hydrogen fumarate: 1.07 g of base in 20 ml of EtOH is stirred at 25° C.;the slight insoluble material is removed by filtration and then 278 mgof fumaric acid in 5 ml of hot alcohol are added to the precedingfiltrate. After slow crystallization, the organic salt of formula 1 iscollected by filtration and dried (m=825 mg; Yd: 40%):

Empirical formula: C₂₈H₃₅F₂N₃O₅S

Molecular mass: 563.65

White crystals

Melting point: 151-152° C.

NMR (d₆-DMSO) δ: 1.5-1.8 (m, 6H), 1.85-1.95 (m, 2H), 2 (s, 3H), 2.25 (t,2H), 2.45-2.65 (m, 2H), 2.9 (s, 3H), 3.05-3.15 (m, 2H), 3.97 (t, 2H),4.1-4.3 (m, 1H), 6.57 (s, 2H), 6.76 (m, 3H), 6.9 (t, 1H), 7.0-7.12 (m,1H), 7.2 (t, 2H), 7.44 (q, 1H), 12-13 (m, 2H).

EXAMPLE 22-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-1-methyl-3-phenylisothioureahydrogen fumarate (2)

A solution of 2 g (4.61 mmol) of1-methyl-3-phenyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]thiourea(prepared in Example 1.1) in 30 ml of ethanol is treated with 387 μl(754 mg or 4.84 mmol) of iodoethane and stirred overnight at 25° C.,then an additional 199 μl of iodoethane are again added and the mixtureis stirred for a further 24 h. The mixture is evaporated to dryness; aninsoluble material, formed by the hydroiodide of the starting thiourea,is removed by tritutration in ether. The ethereal filtrate is evaporatedto dryness and the residue is taken up in methylene chloride and a 2Nsodium hydroxide solution. The phases are separated and the aqueousphase is reextracted with CH₂Cl₂. The combined organic phase is washedwith water and with aqueous saline solution, dried over anhydrous sodiumsulfate and evaporated to dryness and the residue is purified by flashchromatography in the usual way to give a pale yellow oil (m=1.3 g, Yd:61%); the base is subsequently salified with fumaric acid as describedin Example 1.2 to give 1.31 g (Yd 48%) of crystals of formula 2.

Empirical formula: C₂₉H₃₇F₂N₃O₅S

Molecular mass: 577.57

White crystals

Melting point: 151-152° C.

NMR (d₆-DMSO) δ: 1.05 (t, 3H), 1.5-1.8 (m, 6H), 1.80-2.05 (m, 2H), 2.23(t, 2H), 2.38 (q, 2H), 2.45-2.6 (m, 2H), 2.9 (s, 3H), 3.05-3.15 (m, 2H),3.97 (t, 2H), 4.2-4.4 (m, 1H), 6.75 (s, 2H), 6.76 (d, 2H), 6.90 (t, 1H),7-7.1 (m, 1H), 7.2 (t, 2H), 7.33 (q, 1H).

EXAMPLE 31-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothioureahydrogen fumarate (3)

3.1) 4-Ethylamino-1-[4-(3,4-difluorophenoxy)butyl]piperidinehydrochloride (3.1)

A solution of 6 g of 1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-one(21.2 mmol), prepared as described in Patent WO 97/05134, in a mixtureof 70 ml of CH₂Cl₂ and 5 ml of MeOH is treated with 1.73 g (21.2 mmol)of ethylamine hydrochloride. The mixture is stirred for 2 h at 25° C.and then cooled on an ice bath, and then 5.39 g (25.4 mmol) of sodiumtriacetoxyborohydride and 1.25 ml of acetic acid are added dropwise.After stirring for 1 h at 0° C., the mixture is allowed to return to 25°C. and is stirred overnight at this temperature. The reaction mixture ispoured into ice and basified (with 2N sodium hydroxide) to pH=12.Extraction is carried out several times with methylene chloride and thenthe extract is washed with water and with aqueous saline solution. Afterdrying over anhydrous sodium sulfate, the inorganic salt is removed andthe filtrate is evaporated to dryness to give 6.5 g of brown oil. Thisoil is taken up in 40 ml of ethanol and salified with an ethanolichydrochloric acid solution to give 5.8 g (Yd: 71%) of compound offormula 3.1.

Empirical formula: C₁₇H₂₈Cl₂F₂N₂O

Molecular mass: 385.33

Off-white crystals

Melting point (dec.) 200° C.

NMR (d₆-DMSO) δ: 1.22 (t, 3H), 1.6-2.4 (m, 8H), 2.8-3.7 (m, 9H), 3.99(t, 2H), 6.72-6.82 (m, 1H), 6.95-7.15 (m, 1H), 7.35 (q, 1H), 9.2-9.7 (m,2H), 10.5-11.6 (m, 1H).

3.2)1-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-phenylthiourea(3.2)

By using the procedure described in Example 1.1 but starting from 1.4 g(10.4 mmol) of the preceding compound 3.1, the thiourea of formula 3.2is prepared with a yield of 83%:

Empirical formula: C₂₄H₃₁F₂N₃OS

Molecular mass: 447.57

Light beige powder

Melting point: 133-134° C.

NMR (d₆-DMSO) δ: 1.15 (t, 3H), 1.4-1.8 (m, 8H), 1.85-2 (m, 2H), 2.31 (t,2H), 3.6 (q, 2H), 3.98 (t, 2H), 5.03 (m, 1H), 6.7-6.8 (m, 1H), 7.02-7.18(m, 2H), 7.2-7.4 (m, 5H), 8.89 (s, 1H).

3.3)1-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothioureahydrogen fumarate (3)

By carrying out the preparation as described in Example 1.2 startingfrom 2 g of the preceding thiourea 3.2, the compound of formula 3 isprepared with a yield of 48%:

Empirical formula: C₂₉H₃₇F₂N₃O₅S

Molecular mass: 577.67

White crystals

Melting point: 120-121° C.

NMR (d₆-DMSO) δ: 1.12 (t, 3H), 1.5-1.95 (m, 6H), 1.90 (s, 3H), 2.23 (t,2H), 2.45-2.6 (m, 2H), 3.10 (d, d, 2H), 3.25-3.6 (m, 2H), 3.97 (t, 2H),4.1-4.3 (m, 1H), 6.57 (s, 2H), 6.7-6.85 (m, 2H), 6.89 (t, 1H), 7.02-7.1(m, 1H), 7.23 (t, 2H), 7.28-7.4 (t d, 1H).

EXAMPLE 41-Isobutyl-1-[1-[4-(3,4-difluorophenoxy)butyl]-piperidin-4-yl]-2-methyl-3-phenylisothioureahydrogen fumarate (4)

4.1) 4-Isobutylamino-1-[4-(3,4-difluorophenoxy)butyl]piperidinedihydrochloride (4.1)

The reductive amination, carried out as described in Example 3.1 butstarting from 1.67 ml (1.3 g or 16.8 mmol) of isobutylamine, makes itpossible to prepare 5.2 g (Yd 75%) of the dihydrochloride of formula4.1:

Empirical formula: C₁₉H₃₂Cl₂F₂N₂O

Molecular mass: 413.38

Off-white crystals

Melting point (dec.): >205° C.

NMR (d₆-DMSO) δ: 0.96 (d, 6H), 1.6-1.85 (m, 4H), 1.9-2.15 (m, 2H),2.2-2.3 (m, 2H), 2.7-3.25 (m, 7H), 3.5-3.7 (m, 2H), 3.99 (t, 2H),6.6-6.8 (m, 1H), 7.03-7.12 (m, 1H), 7.3-7.4 (m, 1H), 9-9.3 (m, 2H),10.6-11 (m, 1H).

4.2)1-Isobutyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-phenylthiourea(4.2)

The condensation of 1 g (7.4 mmol) of phenyl isothiocyanate with 3.06 g(7.4 mmol) of the preceding compound 4.1 according to the protocol ofExample 1.7 gives 3.88 g (Yd 91%) of the corresponding thiourea offormula 4.2:

Empirical formula: C₂₆H₃₅F₂N₃OS

Molecular mass: 475.62

Off-white crystals

Melting point: 132° C.

NMR (d₆-DMSO) δ: 0.87 (d, 6H), 1.45-1.8 (m, 8H), 1.9 (t, 2H), 2-2.2 (m,1H), 2.3 (t, 2H), 2.85-3 (m, 2H), 3.2-3.5 (m, 2H), 3.98 (t, 2H), 5 (m,1H), 6.7-6.85 (m, 1H), 7-7.15 (m, 2H), 7.2-7.48 (m, 5H), 8.98 (s, 1H).

4.3)1-Isobutyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothioureahydrogen fumarate (4)

The S-methylation of 1.5 g (3.15 mmol) of the preceding thiourea 4.2according to the protocol of Example 1.2 gives 620 mg (Yd: 34%) of theisothiourea of formula 4:

Empirical formula: C₃₁H₄₁F₂N₃O₅S

Molecular mass: 605.73

White crystals

Melting point: 131-132° C.

NMR (d₆-DMSO) δ: 0.84 (d, 6H), 1.5-2.05 (m, 9H), 2.01 (s, 3H), 2.134 (t,2H), 2.45-2.6 (m, 2H), 3.05-3.15 (m, 4H), 3.97 (t, 2H), 4-4.1 (m, 1H),6.58 (s, 2H), 6.7-6.8 (m, 3H), 6.91 (t, 1H), 7-7.09 (m, 1H), 7.22 (t,2H), 7.28-7.4 (m, 1H), 11-13 (m, 2H).

EXAMPLE 51,2-Dimethyl-1-[1-[5-(3,4-difluorophenoxy)pentyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (5)

5.1) 1-[5-(3,4-Difluorophenoxy)pentyl]piperidin-4-one (5.1)

The condensation of 14 g (50 mmol) of4-(5-bromopentyloxy)-1,2-difluorobenzene with 7.13 g (50 mmol) of1,4-dioxa-8-azaspiro[4.5]decane according to the process of Ismaiel A.M. et al. (J. Med. Chem., 1993, 36, 2519-25) gives, after deprotection,13.6 g (Yd 91%) of an orangy oil of formula 5.1:

Empirical formula: C₁₆H₂₁F₂NO₂

Molecular mass: 297.34

NMR (CDCl₃) δ: 1.5-1.9 (m, 8H), 3-2.8 (m, 8H), 3.8-4 (m, 2H), 6.5-6.6(m, 1H), 6.65-6.75 (m, 1H), 7-7.1 (m, 1H).

5.2) 1-[5-(3,4-Difluorophenoxy)pentyl]-4-methylamino]piperidinedihydrochloride 5.2

By starting from 10 g (33.6 mmol) of the preceding ketone 5.1 and 2.27 g(33.6 mmol) of methylamine hydrochlorde and by carrying out thereductive amination under the same conditions as those of Example 3.1,7.8 g (Yd: 74%) of compound 5.2 are prepared:

Empirical formula: C₁₇H₂₈Cl₂F₂N₂O

Molecular mass: 385.33

Cream crystals

Melting point (dec.): 202-205° C.

NMR (d₆-DMSO) δ: 1.3-1.45 (m, 2H), 1.65-1.8 (m, 4H), 1.9-2.05 (m, 2H),2.2-2.6 (m, 2H), 2.51 (d, 3H), 2.85-3 (m, 5H), 3.5-3.6 (m, 2H), 3.97 (t,2H), 6.7-6.8 (m, 1H), 7-7.12 (m, 1H), 7.34 (t.d, 1H), 9.2-9.7 (m, 2H),10.6-11.2 (m, 1H).

5.3)1-[1-[5-(3,4-Difluorophenoxy)pentyl]piperidin-4-yl]-1-methyl-3-phenylthiourea(5.3)

By applying the protocol of Example 1.1 to 1 g (7.4 mmol) of thepreceding diamine 5.2, the compound of formula 5.3 is prepared with ayield of 91%:

Empirical formula: C₂₄H₃₁F₂N₃OS

Molecular mass: 447.57

Cream crystals

Melting point: 90° C.

NMR (CDCl₃) δ: 1.4-1.6 (m, 4H), 1.7-1.9 (m, 6H), 2.1-2.2 (m, 2H),2.3-2.5 (m, 2H), 2.9-3.1 (m, 5H), 3.9 (t, 2H), 5.2 (m, 1H), 6.5-6.6 (m,1H), 6.64-6.75 (m, 1H), 7-7.1 (m, 2H), 7.15-7.3 (m, 3H), 7.3-7.6 (m,2H).

5.4)1,2-Dimethyl-1-[1-[5-(3,4-difluoro-phenoxy)pentyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (5)

By reaction of 1.5 g of the preceding thiourea with 230 μl of methyliodide according to the process of Example 1.2, 600 mg (Yd: 37%) ofwhite crystals of formula 5 are prepared:

Empirical formula: C₂₉H₃₇F₂N₃O₅S

Molecular mass: 577.67

White powder

Melting point: 129-130° C.

NMR (d₆-DMSO) δ: 1.3-1.45 (m, 2H), 1.45-1.6 (m, 2H), 1.65-1.75 (m, 4H),1.8-1.91 (m, 2H), 2 (s, 3H), 2.24 (t, 2H), 2.4-2.6 (m, 2H), 2.9 (s, 3H),3.10 (d, 2H), 3.95 (t, 2H), 4.1-4.3 (m, 1H), 6.57 (s, 2H), 6.76 (d, 3H),6.9 (t, 1H), 7.01-7.09 (m, 1H), 7.21 (t, 2H), 7.33 (q, 1H).

EXAMPLE 61,2-Dimethyl-1-[1-[3-(3,4-difluorophenoxy)propyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (6)

6.1)1-[1-[3-(3,4-Difluorophenoxy)propyl]piperidin-4-yl]-1-methyl-3-phenylthiourea(6.1)

The condensation of 2 g (14.8 mmol) of phenyl isothiocyanate with 5.3 g(14.8 mmol) of1-[3-(3,4-difluorophenoxy)propyl]-4-(methylamino)piperidinedihydrochloride (cf. WO 97/05134) according to the process of Example1.1 gives 5.5 g (Yd: 88%) of base thiourea crystals of formula 6.1:

Empirical formula: C₂₂H₂₇F₂N₃OS

Molecular mass: 419.524

Off-white crystals

Melting point: 114-115° C.

NMR (CDCl₃) δ: 1.7-2.03 (m, 6H), 2.15 (t, 2H), 2.51 (t, 2H), 3-3.05 (m,2H), 3.04 (s, 3H), 3.96 (t, 2H), 5.1-5.25 (m, 1H), 6.5-6.6 (m, 1H),6.65-6.78 (m, 1H), 7-7.1 (m, 2H), 7.15-7.28 (m, 3H), 7.35 (t, 2H).

The hydrogen fumarate of the preceding base 6.1, prepared in the usualway in ethanol, melts at 159° C.

6.2)1,2-Dimethyl-1-[1-[3-(3,4-difluorophenoxy)propyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (6)

The S-methylation of 1.5 g (3.58 mmol) of the preceding thiourea 6.1with 245 μl methyl iodide according to the protocol of example 1.2 gives615 mg (Yd: 32%) of compound 6 of formula:

Empirical formula: C₂₇H₃₃F₂N₃O₅S

Molecular mass: 549.62

White crystals

Melting point: 106-107° C.

NMR (d₆-DMSO) δ: 1.66-1.7 (m, 2H), 1.75-1.95 (m, 4H), 2 (s, 3H),2.05-2.2 (m, 2H), 2.45-2.6 (m, 2H), 2.9 (s, 3H), 3-3.1 (m, 2H), 4 (t,2H), 4.07-4.25 (m, 1H), 6.59 (s, 2H), 6.76 (d, 3H), 6.9 (t, 1H),7.02-7.1 (m, 1H), 7.20 (t, 2H), 7.33 (q, 1H), 12-14 (m, 2H).

EXAMPLE 71,2-Dimethyl-1-[1-[4-(4-fluorophenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (7)

7.1)1-Methyl-1-[1-[4-(4-fluorophenoxy)butyl]piperidin-4-yl]-3-phenylthiourea(7.1)

The condensation of 2 g (14.8 mmol) of phenyl isothiocyanate with 5.25 g(14.8 mmol) of 1-[4-(4-fluorophenoxy)butyl]-4-methylaminopiperidinedihydrochloride (cf. WO 97/05134) according to the protocol of Example1.1 provides 5.5 g (Yd: 90%) of white crystals of formula 7.1:

Empirical formula: C₂₃H₃₀FN₃OS

Molecular mass: 415.55

White crystals

Melting point: 161-162° C.

Hydrogen fumarate: M.p.=167° C.

NMR (d₆-DMSO) δ: 1.5-1.8 (m, 8H), 1.93 (t, 2H), 2.32 (t, 2H), 2.94 (d,2H), 3.03 (s, 3H), 3.95 (t, 2H), 5.02 (m, 1H), 6.9-6.97 (m, 2H),7.05-7.15 (m, 3H), 7.25-7.31 (m, 4H), 8.97 (s, 1H).

7.2)1,2-Dimethyl-1-[1-4-(4-fluorophenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (7)

The S-methylation of 1.5 g (3.6 mmol) of the preceding compoundaccording to the procedure of Example 1.2 gives 620 mg (Yd: 32%) ofwhite crystals of formula 7:

Empirical formula: C₂₈H₃₆FN₃O₅S

Molecular mass: 545.66

White crystals

Melting point: 133-134° C.

NMR (d₆-DMSO) δ: 1.5-1.73 (m, 6H), 1.8-1.93 (m, 2H), 2 (s, 3H), 2.24 (t,2H), 2.4-2.6 (m, 2H), 2.89 (s, 3H), 3.05-3.5 (m, 1H), 3.95 (t, 2H),4.1-4.3 (m, 1H), 6.58 (s, 2H), 6.76 (d, 2H), 6.8-7 (m, 3H), 7.05-7.15(m, 2H), 7.20 (t, 2H).

EXAMPLE 81,2-Dimethyl-1-[1-[2-(4-fluorophenoxy)ethyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (8)

8.1)1-Methyl-1-[1-[2-(4-fluorophenoxy)ethyl]piperidin-4-yl-3-phenylthiourea(8.1)

The reaction of 680 mg (5 mmol) of phenyl isothiocynate with 1.63 g (5mmol) of 1-[2-(4-fluorophenoxy)ethyl]-4-(methylamino)piperidinedihydrochloride according to the protocol of Example 1.2 gives 1.73 g(Yd: 89%) of beige powder of formula 8.1

Empirical formula: C₂₁H₂₆FN₃OS

Molecular mass: 387.50

Beige powder

Melting point: 142° C.

NMR (CDCl₃) δ: 1.72-1.9 (m, 4H), 2.3 (t.d, 2H), 2.81 (t, 2H), 3.07 (s,3H), 3.05-3.12 (m, 2H), 4.06 (t, 2H), 5.1-5.2 (m, 1H), 6.84 (d.d, 2H),6.97 (t, 2H), 7.04 (s, 1H), 7.15-7.27 (m, 3H), 7.34 (t, 2H)

8.2)1,2-Dimethyl-1-[1-[2-(4-fluorophenoxy)ethyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (8)

By starting from 1.71 g (4.4 mmol) of the preceding thiourea 8.1 and byalkylating it with 290 μl of methyl iodide, 712 mg (Yd: 31%) of whitecrystals of formula 8 are prepared:

Empirical formula: C₂₆H₃₂FN₃O₅S

Molecular mass: 517.60

White crystals

Melting point: 120° C.

NMR (d₆-DMSO) δ: 1.5-1.7 (m, 2H), 1.75-1.9 (m, 2H), 1.99 (s, 3H), 2.20(t, 2H), 2.75 (t, 2H), 2.9 (s, 3H), 3.07 (d, 2H), 4.06 (t, 2H), 4.1-4.25(m, 1H), 6.61 (s, 2H), 6.76 (d, 2H), 6.9 (t, 1H), 6.92-6.98 (m, 2H),7.05-7.15 (m, 2H), 7.20 (t, 2H), 12-14 (m, 2H).

EXAMPLE 9

1,2-Dimethyl-1-[1-[4-(4-methoxyphenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (9)

9.1) 1-[4-(4-Methoxyphenoxy)butyl]-4-(methylamino)piperidinedihydrochloride (9.1)

The reductive amination of 6 g (21.6 mmol) of1-[4-(4-methoxyphenoxy)butyl]-4-piperidone (prepared according toIsmaiel et al., J. Med. Chem., 1993, 36, 2519-25) in the presence of1.35 g (20 mmol) of methylamine hydrochloride and 4.6 g (21.6 mmol) ofsodium triacetoxyborohydride according to the description of Example3.1, makes it possible to prepare 5.3 g (Yd: 67%) of white powder offormula 9.1:

Empirical formula: C₁₇H₃₀Cl₂N₂O₂

Molecular mass: 365.34

White powder

NMR (d₆-DMSO) δ: 1.5-2.3 (m, 8H), 2.85-3.25 (m, 5H), 3.33 (s, 3H),3.52-3.62 (m, 2H), 3.7 (s, 3H), 3.92 (d, 2H), 6.8-6.9 (m, 4H), 9.3-9.6(m, 2H), 10.5-11 (m, 1H).

9.2)1-Methyl-1-[1-[4-(4-methoxyphenoxy)butyl]piperidin-4-yl]-3-phenylthiourea(9.2)

The addition of 2.5 g (6.84 mmol) of the preceding compound 9.1 to 925mg (6.84 mmol) of phenyl isothiocyanate according to the protocol ofExample 1.1 gives 2.70 g (Yd: 92%) of the thiourea of formula 9.2:

Empirical formula: C₂₄H₃₃N₃O₂S

Molecular mass: 427.58

Beige powder

Melting point: 111° C.

NMR (CDCl₃) δ: 1.65-2.7 (m, 12H), 3.06 (s, 3H), 3.06-3.25 (m, 2H), 3.77(s, 3H), 3.93 (t,2H), 5.3 (m, 1H), 6.83 (s, 4H), 7.08 (s, 1H), 7.15-7.3(m, 3H), 7.33 (t, 2H).

9.3)1,2-Dimethyl-1-[1-[4-(4-methoxyphenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (9)

The S-methylation of 1.5 g (3.5 mmol) of the preceding thiourea 9.2 with240 μl of methyl iodide according to 1.2 results in the preparation of690 mg (Yd: 35%) of the isothiourea of formula 9:

Empirical formula: C₂₉H₃₉N₃O₆S

Molecular mass: 557.689

White crystals

Melting point: 120° C.

NMR (d₆-DMSO) δ: 1.5-1.75 (m, 6H), 1.8-1.87 (m, 2H), 2 (s, 3H), 2.35-2.7(m, 2H), 2.9 (s, 3H), 3.09 (d, 2H), 3.69 (s, 3H), 3.91 (t, 2H), 4.12-4.3(m, 1H), 6.58 (s, 2H), 6.77 (d, 2H), 6.8-6.95 (m, 5H), 7.21 (t, 2H).

EXAMPLE 101,2-Dimethyl-1-(1-[4-(3,4-dimethylphenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (10)

10.1) 1-[4-(3,4-Dimethylphenoxy)butyl]-4-(methylamino)piperidinedihydrochloride (10.1)

1,4-Dibromobutane, condensed with 3,4-dimethylphenol according toIsmaïel et al. (J. Med. Chem., 1993, 36, 2519-25), gives1-[4-bromobutoxy]-3,4-dimethylbenzene with a yield of 86%. Thecondensation of this compound (according to the same authors) with1,4-dioxa-8-azaspiro[4.5]decane gives, after deprotection,1-[4-(3,4-dimethylphenoxy)butyl]-4-piperidone in the form of an orangeyoil with a yield of 61%. The reductive amination of this ketone (4.33 gor 15.7 mmol) with methylamine hydrochloride (1.06 g; 15.7 mmol) in thepresence of sodium triacetoxyborohydride (4.33 g; 20.5 mmol) accordingto the protocol of Example 3.1 makes it possible to prepare 5.95 g (Yd:63%) of the compound of formula 10:

Empirical formula: C₁₈H₃₂Cl₂N₂O

Molecular mass: 362.37

White powder

Melting point: (decomp.) 195-198° C.

NMR (d₆-DMSO) δ: 1.5-2.1 (m, 6H), 2.13 (s, 3H), 2.18 (s, 3H), 2.18-2.3(m, 2H), 2.8-3.2 (m, 4H), 3.33 (m, 3H), 3.4-3.7 (m, 2H), 3.93 (t, 2H),6.6-6.7 (m, 1H), 6.73 (s, 1H), 7/02 (d, 1H), 9.3-9.7 (m, 2H), 10.5-11(m, 1H).

10.2)1-Methyl-1-[1-[4-(3,4-dimethylphenoxy)butyl]piperidin-4-yl]-3-phenylthiourea(10.2)

The application of the process of Example 1.1 to 2.69 g (7.4 mmol) ofthe preceding amine (10.1) and to 1 g (7.40 mmol) of phenylisothiocyanate makes it possible to prepare 2.81 g (Yd: 89%) of thecompound of formula 10.2:

Empirical formula: C₂₅H₃₅N₃OS

Molecular mass: 425.61

Off-white powder

Melting point: 107° C.

NMR (CDCl₃) δ: 1.55-1.95 (m, 8H), 2.1-2.25 (m, 2H), 2.19 (s, 3H), 2.23(s, 3H), 2.45 (t, 2H), 2.95-3.1 (m, 2H), 3.04 (s, 3H), 3.94 (t, 2H), 5.2(m, 1H), 6.63 (dd, 1H), 6.7 (d, 1H), 7-7.06 (m, 2H), 7.1-7.27 (m, 3H),7.36 (t, 2H).

10.3)1,2-Dimethyl-1-[1-[4-(3,4-dimethylphenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (10)

A solution of 1 g (2.35 mmol) of the preceding thiourea (10.2) in 10 mlof DMF is treated at 25° C. with 245 μl of dimethyl sulfate, stirredovernight at 25° C. and then heated for 1 h at 60° C. The mixture isevaporated to dryness and the residue is recovered in the usual way andpurified by flash chromatography to give 325 mg (Yd: 32%) of a lightyellow oil. This oil is taken up in ethanol and salified with a solutionof 80 mg of fumaric acid in the same solvent to give 340 mg (Yd: 26%) ofcompound of formula:

Empirical formula: C₃₀H₄₁N₃O₅S

Molecular mass: 555.72

White crystals

Melting point: 138-139° C.

NMR (d₆-DMSO) δ: 1.5-1.7 (m, 6H), 1.75-1.95 (m, 2H), 2 (s, 3H), 2.1-2.21(m, 2H), 2.12 (s, 3H), 2.2 (s, 3H), 2.4-2.6 (m, 2H), 2.89 (s, 3H),3.02-3.2 (m, 2H), 3.92 (t, 2H), 4.1-4.3 (m, 1H), 6.58 (s, 2H), 6.63 (dd,1H), 6.7-6.8 (m, 3H), 6.9 (t, 1H), 7 (d, 1H), 7.2 (t, 2H).

EXAMPLE 111,2-Dimethyl-1-[1-[4-(2-methoxy-4-chlorophenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (11)

11.1) 1-[4-(2-Methoxy-4-chlorophenoxy)butyl]-4-(methylamino)piperidinedihydrochloride (11.1)

The condensation of 1,4-dibromobutane with 2-methoxy-4-chlorophenolgives, according to Ismaiel et al.,1-(4-bromobutoxy)-2-methoxy-4-chlorobenzene with a yield of 86%. Thealkylation of 1,4-dioxa-8-azaspiro[4.5]decane by this derivativeprovides, after deprotection,1-[4-(2-methoxy-4-chlorophenoxy)butyl]-4-piperidone with a yield of 96%.The reductive amination of 4.7 g (˜15 mmol) of the preceding ketone withmethylamine hydrochloride (1.02 g) in the presence of 4.15 g (19 mmol)of sodium triacetoxyborohydride according to Example 3.1 gives 3.92 g(Yd: 65%) of compound 11.1 of formula:

Empirical formula: C₁₇H₂₉Cl₃N₂O₂

Molecular mass: 399.79

Light yellow powder

NMR (d₆-DMSO) δ: 1.5-2.27 (m, 8H), 2.51 (s, 3H), 2.8-3.25 (m, 5H),3.4-3.6 (m, 2H), 3.8 (s, 3H), 3.97 (t, 2H), 6.92 (dd, 1H), 6.96-6.99 (m,1H), 7.02 (d, 1H), 9.3-9.7 (m, 2H), 10.2-11.1 (m, 1H).

11.2)1-Methyl-1-[1-[4-(2-methoxy-4-chlorophenoxy)butyl]piperidin-4-yl]-3-phenylthiourea(11.2)

The application of the procedure of 1.1 to 2.85 g (7.13 mmol) of thepreceding diamine 11.1 results in the formation of 2.98 g (Yd: 90%) ofthe thiourea of formula 11.2:

Empirical formula: C₂₄H₃₂ClN₃O₂S

Molecular mass: 462.04

Light beige crystals

Melting point: 129° C.

NMR (CDCl₃) δ: 1.5-2.1 (m, 8H), 2.1-2.3 (m, 2H), 2.35-2.6 (m, 2H), 3.04(s, 3H), 3-3.2 (m, 2H), 3.85 (s, 3H), 4.01 (t, 2H), 5.24 (m, 1H), 6.78(d, 1H), 6.8-6.9 (m, 2H), 7.06 (s, 1H), 7.1-7.29 (m, 3H), 7.35 (t, 2H).

11.3)1,2-Dimethyl-1-[1-[4-(2-methoxy-4-chlorophenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (11)

The S-methylation of 1.2 g (2.6 mmol) of the preceding thiourea 11.2according to the process of Example 1.2 gives 618 mg (Yd: 40%) of thederivative of formula 11:

Empirical formula: C₂₉H₃₈ClN₃O₆S

Molecular mass: 592.13

Off-white crystals

Melting point: 106-107° C.

NMR (d₆ DMSO) δ: 1.5-1.82 (m, 6H), 1.84-1.97 (m, 2H), 2 (s, 3H), 2.35(t, 2H), 2.61 (t, 2H), 2.96 (s, 3H), 3.16 (d, 2H), 3.94 (s, 3H), 3.96(t, 2H), 4.15-4.35 (m, 1H), 6.59 (s, 2H), 6.76 (d, 2H), 6.8-7.1 (m, 4H),7.21 (t, 2H), 12-14 (m, 2H).

EXAMPLE 121,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2-fluorophenyl)isothioureahydrogen fumarate (12)

12.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2-fluorophenyl)thiourea(12.1)

The application of the protocol of Example 1.1 to 610 mg (4 mmol) of2-fluorophenyl isothiocyanate and 1.20 g (4 mmol) of1-[4-(3,4-difluorophenoxy)butyl]-4-(methylamino)piperidine gives 1.65 g(Yd: 91%) of white crystals of formula 12.1:

Empirical formula: C₂₃H₂₈F₃N₃OS

Molecular mass: 451.54

White crystals

Melting point: 126° C.

NMR (CDCl₃) δ: 1.5-1.95 (m, 8H), 2.13 (t, 2H), 2.42 (t, 2H), 3-3.06 (m,2H), 3.11 (s, 3H), 3.94 (t, 2H), 5.21 (m, 1H), 6.5-6.6 (m, 1H), 6.5-6.75(m, 1H), 6.92 (s, 1H), 6.8-7.3 (m, 4H), 7.75-8.01 (m, 1H).

12.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2-fluorophenyl)isothioureahydrogen fumarate (12)

200 mg (3.54 mmol) of CaO and 242 μl (3.9 mmol) of methyl iodide areadded to a solution of 1.60 g (3.54 mmol) of the preceding thiourea 12.1in 20 ml of chloroform and then the mixture is brought to reflux for 3hours. The mixture is filtered, then washed with water and with aqueoussaline solution, and dried on anhydrous sodium sulfate. After removingthe inorganic salt, the filtrate is evaporated to dryness and purifiedby flash chromatography, elution being carried out with a 95/4.5/0.5CHCl₃/MeOH/NH₄OH mixture. 1.1 g of oil are recovered, which oil issalified in the usual way to give 790 mg (Yd: 39%) of the compound offormula 12:

Empirical formula: C₂₈H₃₄F₃N₃O₅S

Molecular mass: 581.64

White crystals

Melting point: 148° C.

NMR (d₆-DMSO) δ: 1.5-1.75 (m, 6H), 1.78-1.9 (m, 2H), 2.08 (s, 3H), 2.15(t, 2H), 2.41-2.6 (m, 2H), 2.93 (s, 3H), 3.01-3.09 (m, 2H), 3.97 (t,2H), 4.13-4.25 (m, 1H), 6.58 (s, 2H), 6.72-6.79 (m, 1H), 6.81-6.87 (m,1H), 6.9-6.95 (m, 1H), 7.0-7.1 (m, 3H), 7.33 (q, 1H), 12-14 (m, 2H).

EXAMPLE 131,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-fluorophenyl)isothioureahydrogen fumarate (13)

13.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-fluorophenyl)thiourea(13.1)

The condensation of 1.2 g (4 mmol) of1-[4-(3,4-difluorophenoxy)butyl]-4-(methylamino)piperidine with 0.61 g(4 mmol) of 4-fluorophenyl isothiocyanate in THF according to theprotocol of Example 1.1 gives 1.75 g (Yd: 95%) of a powder of formula13.1

Empirical formula: C₂₃H₂₈F₃N₃OS

Molecular mass: 451.54

White powder

Melting point: 133° C.

NMR (CDCl₃) δ: 1.5-1.9 (m, 8H), 2.13 (t, 2H), 2.42 (t, 2H), 3-3.1 (m,2H), 3.06 (s, 3H), 3.92 (t, 2H), 5.23 (m, 1H), 6.5-6.6 (m, 1H),6.65-6.67 (m, 1H), 6.94 (s, 1H), 7-7.08 (m, 3H), 7.2-7.3 (m, 2H).

13.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-fluorophenyl)isothioureahydrogen fumarate (13)

The isothiourea 13 is prepared according to Example 1.2 with a yield of21% by S-methylation of 1.2 g (2.65 mmol) of the preceding thiourea13.1.

Empirical formula: C₂₈H₃₄F₃N₃O₅S

Molecular mass: 581.64

White crystals

Melting point: 125° C.

NMR (d₆-DMSO) δ: 1.5-1.73 (m, 6H), 1.74-1.9 (m, 2H), 2.02 (s, 3H), 2.15(t, 2H), 2.4-2.6 (m, 2H), 2.89 (s, 3H), 3-3.1 (m, 2H), 3.97 (t, 2H),4.1-4.25 (m, 1H), 6.5 (s, 2H), 6.7-6.8 (m, 3H), 6.95-7.1 (m, 3H),7.25-7.4 (m, 1H), 11-13 (m, 2H).

EXAMPLE 141,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-chlorophenyl)isothioureahydrogen fumarate (14)

14.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-chlorophenyl)thiourea(14.1)

By starting from 0.85 g (5 mmol) of 4-chlorophenyl isothiocyanate and1.5 g (5 mmol) of1-[4-(3,4-difluorophenoxy)butyl]-4-(methylamino)piperidine in 30 ml ofTHF, 2.16 g (Yd: 92%) of compound 14.1 is prepared according to theprocess of Example 1.1, compound 14.1 having the formula:

Empirical formula: C₂₃H₂₈ClF₂N₃OS

Molecular mass: 467.99

Off-white crystals

Melting point: 149° C.

(Melting point of the hydrogen fumarate: 166° C.)

NMR (CDCl₃) δ: 1.5-2 (m, 8H), 2.14 (t, 2H), 2.43 (t, 2H), 3-3.1 (m, 2H),3.06 (s, 3H), 3.92 (t, 2H), 5.12 (m, 1H), 6.5-6.6 (m, 1H), 6.62-6.75 (m,1H), 6.95 (s, 1H), 7-7.08 (m, 1H), 7.22 (d, 2H), 7.31 (d, 2H).

14.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxybutyl]piperidin-4-yl]-3-(4-chlorophenyl)isothioureahydrogen fumarate (14)

By using the process of Example 1.2, by heating a mixture of 1.65 g (3.5mmol) of the preceding thiourea 14.1 and 240 μl of methyl iodide (3.85mmol) in 30 ml of ethanol at 40° C. for 2 h, the compound 14 is preparedwith a yield of 36%, the compound 14 having the formula:

Empirical formula: C₂₈H₃₄ClF₂N₃O₅S

Molecular mass: 598.09

Pulverulent white crystals

Melting point: 130° C.

NMR (d₆-DMSO) δ: 1.5-1.75 (m, 6H), 1.77-1.9 (m, 2H), 2.03 (s, 3H), 2.18(t, 2H), 2.4-2.6 (m, 2H), 2.9 (s, 3H), 3.07 (d, 2H), 3.97 (t, 22H),4.1-4.2 (m, 1H), 6.58 (s, 2H), 6.7-6.8 (m, 3H), 7-7.09 (m, 1H), 7.2-7.3(m, 2H), 7.3-7.4 (m, 1H).

EXAMPLE 151,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methylphenyl)isothioureahydrogen fumarate (15)

15.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methylphenyl)thiourea(15.1)

The replacement of phenyl isothiocyanate by para-tolyl isothiocyanate(0.60 g; 4 mmol) in the procedure of Example 1.1 with THF as solvantresults, with a yield of 95%, in the thiourea 15.1 of formula:

Empirical formula: C₂₄H₃₁F₂N₃OS

Molecular mass: 447.57

Off-white crystals

Melting point: 151° C.

NMR (CDCl₃) δ: 1.5-1.95 (m, 8H), 2.13 (t, 2H), 2.33 (s, 3H), 2.42 (t,2H), 2.95-3.1 (m, 5H), 3.92 (t, 2H), 5.21 (m, 1H), 6.5-6.6 (m, 1H),6.65-6.8 (m, 1H), 6.98 (s, 1H), 7-71 (m, 1H), 7.1-7.17 (m, 4H).

15.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methylphenyl)isothioureahydrogen fumarate (15)

830 mg (Yd: 57%) of crystals of formula 15 are prepared by S-methylationof 1.12 g (2.5 mmol) of the preceding thiourea 15.1 according to theprocess of Example 1.2:

Empirical formula: C₂₉H₃₇F₂N₃O₅S

Molecular mass: 577.67

White crystals

Melting point: 141° C.

NMR (d₆-DMSO) δ: 1.5-1.75 (m, 6H), 1.8-1.9 (m, 2H), 2 (s, 3H), 2.18 (t,2H), 2.23 (s, 3H), 2.42-2.55 (m, 2H), 2.87 (s, 3H), 3.07 (d, 2H), 3.97(t, 2H), 4.1-4.25 (m, 1H), 6.58 (s, 2H), 6.64 (d, 2H), 6.7-6.8 (m, 1H),7.01 (d, 2H), 7.02-7.09 (m, 1H), 7.33 (q, 1H).

EXAMPLE 161,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methoxyphenyl)isothioureahydrogen fumarate (16)

16.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methoxyphenyl)thiourea(16.1)

By using the protocol of Example 1.1 with 4-methoxyphenyl isothiocyanate(660 mg: 4 mmol) as acylating agent in THF, 1.66 g (Yd: 90%) of compound16.1 are prepared, compound 16.1 having the formula:

Empirical formula: C₂₄F₃₁F₂N₃O₂S

Molecular mass: 463.57

Beige powder

Melting point: 122° C.

NMR (CDCl₃) δ: 1.5-1.9 (m, 8H), 2.14 (t, 2H), 2.42 (t, 2H), 2.95-3.12(m, 2H), 3.05 (s, 3H), 3.81 (s, 3H), 3.92 (t, 2H), 5.24 (m, 1H), 6.5-6.6(m, 1H), 6.65-6.75 (m, 1H), 6.88 (d, 2H), 6.94(s, 1H), 7-7.08 (m, 1H),7.17 (d, 2H).

16.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methoxyphenyl)isothioureahydrogen fumarate (16)

The S-alkylation carried out on 1.15 g (2.5 mmol) of the thiourea 16.1according to the process of Example 1.2 gives 692 mg (Yd: 46%) of theisothiourea of formula 16:

Empirical formula: C₂₉H₃₇F₂N₃O₆S

Molecular mass: 593.67

White crystals

Melting point: 130° C.

NMR (d₆-DMSO) δ: 1.4-1.9 (m, 8H), 2 (s, 3H), 2.18 (t, 2H), 2.4-2.6 (m,2H), 2.87 (s, 3H), 3.07 (d, 2H), 3.7 (s, 3H), 3.97 (t, 2H), 4.1-4.25 (m,1H), 6.58 (s, 2H), 6.69 (d, 2H), 6.72-6.85 (m, 3H), 7-7.1 (m, 1H), 7.33(q, 1H).

EXAMPLE 171,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-dimethylphenyl)isothioureahydrogen fumarate (17)

17.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-dimethylphenyl)thiourea(17.1)

The use of 820 mg (5 mmol) of 2,6-dimethylphenyl isothiocyanate in theprotocol of Example 1.1 results in the formation of 1.96 g (Yd 86%) ofthe thiourea of formula 17.1

Empirical formula: C₂₅H₃₃F₂N₃OS

Molecular mass: 461.60

Off-white powder

Melting point: 114° C.

NMR (CDCl₃) δ: 1.5-1.9 (m, 8H), 2.07-2.18 (m, 2H), 2.24 (s, 6H),2.32-2.5 (m, 2H), 3-3.05 (m, 2H), 3.09 (s, 3H), 3.92 (t, 2H), 5.24 (m,1H), 6.5-6.63 (m, 2H), 6.66-6.74 (m, 1H), 6.95-7.2 (m, 4H).

17.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-dimethylphenyl)isothioureahydrogen fumarate (17)

The preceding thiourea 17.1 (1.33 g; 2.88 mmol) is treated according tothe process of 1.2 to give 720 mg (Yd: 42%) of the isothiourea offormula 17:

Empirical formula: C₃₀H₃₉F₂N₃O₅S

Molecular mass: 591.70

Off-white crystals

Melting point: 129° C.

NMR (d₆-DMSO) δ: 1.5-1.8 (m, 6H), 1.8-1.92 (m, 2H), 1.97 (s, 6H), 2.11(s, 3H), 2.19 (t, 2H), 2.4-2.55 (m, 2H), 2.87 (s, 3H), 3.05-3.13 (m,2H), 3.9-4.08 (m, 3H), 6.58 (s, 2H), 6.7-6.8 (m, 2H), 6.94 (d, 2H),7-7.1 (m, 1H), 7.33 (q, 1H).

EXAMPLE 181,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-[2,6-diisopropylphenyl]isothioureahydrogen fumarate (18)

18.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-[2,6-diisopropylphenyl]thiourea(18.1)

2.31 g (Yd: 89%) of the thiourea of formula 18.1 are prepared from 1.10g (5 mmol) of 2,6-diisopropylphenyl isothiocyanate in 20 ml of THFaccording to the protocol of 1.1:

Empirical formula: C₂₉H₄₁F₂N₃OS

Molecular mass: 517.70

Off-white powder

Melting point: 130° C. (Hydrogen fumarate: M.p.=164° C.)

NMR (CDCl₃) δ: 1.16 (d, 6H), 1.29 (d, 6H), 1.45-1.95 (m, 8H), 2-2.25 (m,2H), 2.3-2.5 (m, 2H), 3.03 (t, 2H), 3.14 (s, 3H), 3.93 (t, 2H),6.47-6.62 (m, 2H), 6.65-6.75 (m, 1H), 7.05 (q, 1H), 7.19 (d, 2H),7.26-7.4 (m, 1H).

18.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-[2,6-diisopropylphenyl]isothioureahydrogen fumarate (18)

The S-methylation of 1.50 g (2.9 mmol) of the preceding thiourea 18.1results, by heating for 4 h at 50° according to Example 14.2, in thepreparation of 698 mg (Yd: 37%) of the corresponding S-methylisothiourea 18:

Empirical formula: C₃₄H₄₇F₂N₃O₅S

Molecular mass: 642.82

Off-white powder

Melting point 194° C.

NMR (d₆-DMSO) δ: 1.05 (d, 6H), 1.13 (d, 6H), 1.6-1.85 (m, 6H), 1.9-2.1(m, 2H), 2.18 (s, 3H), 2.7-3 (m, 4H), 2.89 (s, 3H), 3.1-3.7 (m, 4H), 4(t, 2H), 4.04-4.3 (m, 1H), 6.62 (s, 2H), 6.7-6.8 (m, 1H), 6.91 (t, 1H),6.96-7.12 (m, 3H), 7.35 (q, 1H), 11-13 (m, 2H).

EXAMPLE 191,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(3-fluorophenyl)isothioureahydrogen fumarate (19)

19.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(3-fluorophenyl)thiourea(19.1)

The application of the protocol of Example 1.1 to 0.61 g (4 mmol) of3-fluorophenyl isothiocyanate makes it possible to prepare 1.87 g (Yd:94%) of white powder of formula 19.1:

Empirical formula: C₂₃H₂₈F₃N₃OS

Molecular mass: 451.84

White powder

Melting point: 128° C.

NMR (CDCl₃) δ: 1.5-1.9 (m, 8H), 2.13 (s, 2H), 2.35-2.48 (m, 2H), 2.95-3(m, 2H), 3.04 (s, 3H), 3.92 (t, 2H), 5.16 (m, 1H), 6.5-6.6 (m, 1H),6.65-6.72 (m, 1H), 6.88 (m, 1H), 6.95-7.1 (m, 4H), 7.23-7.4 (m, 1H).

19.2)1,2-Dimethyl-1-[1-(4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(3-fluorophenyl)isothioureahydrogen fumarate (19)

The S-methylation of 1.60 g (3.54 mmol) of the thiourea 19.1 gives 880mg (Yd: 42%) of the compound of formula 19:

Empirical formula: C₂₈H₃₄F₃N₃O₆S

Molecular mass: 581.64

White crystals

Melting point: 133° C.

NMR (d₆-DMSO) δ: 1.5-1.9 (m, 8H), 2.03 (s, 3H), 2.14 (t, 2H), 2.46 (t,2H), 2.9 (s, 3H), 3.05 (d, 2H), 3.97 (t, 2H), 4.12-4.25 (m, 1H),6.5-6.63 (m, 4H), 6.67-6.8 (m, 2H), 7-7.1 (m, 1H), 7.23 (q, 1H), 7.33(q, 1H).

EXAMPLE 201,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-nitrophenyl)isothioureahydrogen fumarate (20)

20.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-nitrophenyl)thiourea(20.1)

By condensation of 0.72 g (4 mmol) of 4-nitrophenyl isothiocyanateaccording to Example 1.1, 1.71 g (Yd: 88%) of yellow powder of formula20.1 are prepared:

Empirical formula: C₂₃H₂₈F₂N₄O₃S

Molecular mass: 478.55

Pulverulent yellow crystals

Melting point: 108° C.

NMR (CDCl₃) δ: 1.5-1.95 (m, 8H), 2.14 (t, 2H), 2.35-2.5 (m, 2H), 3-3.15(m, 2H), 3.11 (s, 3H), 3.93 (t, 2H), 5.15 (m, 1H), 6.52-6.62 (m, 1H),6.65-6.78 (m, 1H), 7.05 (q, 1H), 7.16 (s, 1H), 7.45 (d, 2H), 8.2 (d,2H).

20.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-nitrophenyl)isothioureahydrogen fumarate (20)

The S-methylation of 1.60 g (3.34 mmol) of the preceding thiourea 20.1according to Example 12.2 makes it possible to prepare 610 mg (Yd: 30%)of the isothiourea of formula 20:

Empirical formula: C₂₈H₃₄F₂N₄O₇S

Molecular mass: 608.64

Yellow crystals

Melting point: 132° C.

NMR (d₆-DMSO) δ: 1.5-1.74 (m, 6H), 1.75-1.90 (m, 2H), 2.03 (s, 3H), 2.1(t, 2H), 2.46 (t, 2H), 3.05 (s, 3H), 3.1 (d, 2H), 3.97 (t, 2H), 4.2-4.3(m, 1H), 6.59 (s, 2H), 6.74-6.78 (m, 1H), 6.95 (d, 2H), 7-7.1 (m, 1H),7.33 (q, 1H), 8.09 (d, 2H), 12-14 (m, 2H).

EXAMPLE 211,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-difluorophenyl)isothioureahydrogen fumarate (21)

21.1)1-Methyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-difluorophenyl)thiourea(21.1)

The reaction of 1 g (5.84 mmol) of 2,6-difluorophenyl isothiocyanateaccording to the description of Example 1.1 gives 2.88 g (Yd: 81%) ofwhite powder of formula 21.1:

Empirical formula: C₂₃H₂₇F₄N₃OS

Molecular mass: 469.53

Pulverulent white crystals

Melting point: 120° C.

NMR (CDCl₃) δ: 1.5-2 (m, 8H), 2.15 (t, 2H), 2.43 (t, 2H), 3-3.1 (m, 2H),3.15 (s, 3H), 3.92 (t, 2H), 5.19 (m, 1H), 6.39 (s, 1H), 6.5-6.6 (m, 1H),6.65-6.75 (m, 1H), 6.97 (t, 2H), 7.05 (q, 1H), 7.2-7.6 (m, 1H).

21.2)1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-difluorophenyl)isothioureahydrogen fumarate (21)

The reaction of 0.60 g (4.2 mmol) of methyl iodide with 1.88 g (4 mmol)of the preceding thiourea 21.1 in 10 ml of DMF according to the protocolof 1.2 makes it possible to prepare 690 mg (Yd: 29%) of the isothiourea21 of formula:

Empirical formula: C₂₈H₃₃F₄N₃O₅S

Moleculare mass: [lacuna]

White crystals

NMR (d₆-DMSO) δ: 1.6-2.1 (m, 8H), 2.17 (s, 3H), 2.7-2.95 (m, 4H), 3 (s,3H), 3.35-3.45 (m, 2H), 3.99 (t, 2H), 4.3-4.5 (m, 1H), 6.62 (s, 2H),6.7-6.8 (m, 1H), 6.9-7.12 (m, 4H), 7.35 (q, 1H), 11-13 (m, 2H).

EXAMPLE 221,2-Dimethyl-1-[1-[3-[2-(4-fluorophenyl)ethoxy]propyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (22)

22.1) 4-Fluoro-1-[2-(3-chloropropoxy)ethyl]benzene (22.1)

A solution of 86 g (2.14 mol) of NaOH pellets in 86 g of water isstirred, cooled to 25° C. and then treated with 20 g (0.143 mol) of4-fluorophenethyl alcohol, 113 ml (1.14 mol) of 1-bromo-3-chloropropaneand then with 4.85 g (14 mmol) of tetrabutylammonium hydrogen sulfate.Vigorous stirring is maintained for 4 h at 25° C., extraction is thencarried out with ether and the extract is washed with water and withaqueous saline solution and dried over anhydrous sodium sulfate. Afterremoving the inorganic salt, the filtrate is evaporated to dryness andthe residual oil is rectified under vacuum to give 20.3 g (Yd: 65%) ofproduct of formula 22.1:

Empirical formula: C₁₁H₁₄ClFO

Molecular mass: 216.67

Colorless oil

Boiling point: 94-97° C./0.4 mbar.

NMR (CDCl₃) δ: 2.08 (q, 2H), 2.85 (t, 2H), 3.46 (t, 2H), 3.55 (t, 2H),3.63 (t, 2H), 6.97 (t, 2H), 7.1-7.2 (m, 2H).

22.2) 1-[3-[2-(4-Fluorophenyl)ethoxy]propyl]-4-piperidone (22.2)

A solution of 17.5 g (81 mmol) of1-fluoro-4-[2-(3-chloropropyloxy)ethyl]benzene (22.1) in 175 ml of DMFis treated while stirring at 25° C. with 10.4 ml of1,4-dioxa-8-azaspiro[4.5]decane (11.6 g or 81 mmol) and 12.4 g (85 mmol)of a milled mixture of 98/02 K₂CO₃/KI and then the mixture is heated at80° C. for 5 h. The insoluble material is removed by filtration and thesolution obtained is evaporated to dryness under vacuum. The residue ismainly composed of the protected aminoketone of formula 22.2.1, which isnot isolated.

This compound is treated with 160 ml of 6N hydrochloric acid and heatedat 100° for 2 h with stirring. After returning to 25°, the materialswhich cannot be converted to salts are extracted with CH₂Cl₂ and theaqueous phase is separated, cooled to 0° and basified with 10N sodiumhydroxide to pH 12-13. The expected aminoketone is extracted with CH₂Cl₂and then the extract is washed with water and with aqueous salinesolution, dried over anhydrous sodium sulfate, filtered and evaporatedto dryness: 17.3 g (Yd: 76%) of crude residue of formula 22.2 areobtained:

Empirical formula: C₁₆H₂₂FNO₂

Molecular mass: 279.35

Slightly orangey viscous oil

NMR (CDCl₃) δ: 1.5-1.85 (m, 2H), 2.36-2.58 (m, 6H), 2.72 (t, 4H), 2.85(t, 2H), 3.5 (t, 2H), 3.61 (t, 2H), 6.91-7 (m, 2H), 7.1-7.2 (m, 2H).

22.3) 4-Methylamino-1-[3-[2-(4-fluorophenyl)ethoxy]propyl]piperidinedihydrochloride (22.3)

A solution of 14.7 g (52.6 mmol) of the preceding ketoamine (22.2) in150 ml of CH₂Cl₂ is treated with 3.5 g (52.6 mmol) of methylaminehydrochloride and then methanol is added until dissolution is complete.After stirring for 3 h at 25° C., the mixture is cooled on an ice bathand 14.5 g (68.5 mmol) of sodium triacetoxyborohydride are addedportionwise and, finally, 3 ml of acetic acid are added dropwise.Stirring is continued overnight at 25° C. The reaction mixture is pouredinto ice and basified to pH 12-13. The base released is extracted in theusual way to give a greenish oil.

After dissolution in 70 ml of absolute ethanol and treatment at 0° C.with a 2.5N ethanolic hydrochloric acid solution, the salt crystallizesafter initiation and is recovered by filtration to give 13.6 g (Yd: 70%)of crystals of formula 22.3:

Empirical formula: C₁₇H₂₉Cl₂FN₂O

Molecular mass: 367.34

Off-white crystals

NMR (d₆-DMSO) δ: 1.9-2.04 (m, 4H), 2.08-2.28 (m, 2H), 2.5 (s, 3H), 2.8(t, 2H), 2.85-3.1 (m, 4H), 3.17 (m, 1H), 3.45 (t, 2H), 3.5-3.6 (m, 4H),7.11 (t, 2H), 7.25-7.32 (m, 2H), 9.3-9.7 (m, 2H), 10.6-11.08 (m, 1H).

22.4)1-[1-[3-[2-(4-Fluorophenyl)ethoxy]propyl]piperidin-4-yl]-1-methyl-3-phenylthiourea(22.4)

A solution of 736 mg (5.44 mmol) of phenyl isothiocyanate in 15 ml ofethanol is treated with 2 g (5.44 mmol) of the preceding hydrochloride22.3 and then 1.51 ml (10.9 mmol) of triethylamine. After stirring for 1h, the mixture is evaporated to dryness and treated as in Example 1.1 togive 1.88 g (Yd: 81%) of compound of formula 22.4:

Empirical formula: C₂₄H₃₂FN₃OS

Molecular mass: 429.58

Off-white powder

NMR (CDCl₃) δ: 1.82-1.97 (m, 4H), 1.98-2.18 (m, 2H), 2.2-2.41 (m, 2H),2.5-2.68 (m, 2H), 2.84 (t, 2H), 3.07 (s, 3H), 3.08-3.2 (m, 2H), 3.48 (t,2H), 3.6 (t, 2H), 5.32 (m, 1H), 6.97 (t, 2H), 7.11 (s, 1H), 7.12-7.25(m, 5H), 7.25-7.4 (m, 2H).

22.5)1,2-Dimethyl-1-[1-[3-[2-(4-fluorophenyl)ethoxy]propyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate (22)

By carrying out the S-methylation of 1.76 g (4.1 mmol) of the precedingthiourea (22.4) with 281 μl (4.51 mmol) of methyl iodide according tothe process of Example 1.2, 692 mg (Yd: 30%) of compound of formula 22are prepared:

Empirical formula: C₂₉H₃₈FN₃O₅S

Molecular mass: 559.68

White powder

Melting point: 110-111° C.

NMR (d₆-DMSO) δ: 1.64-1.72 (m, 4H), 1.77-1.91 (m, 2H), 2 (s, 3H), 2.16(t, 2H), 2.43 (t, 2H), 2.78 (t, 2H), 2.89 (s, 3H), 2.98-3.08 (m, 2H),3.4 (t, 2H), 3.54 (t, 2H), 4.1-4.25 (m, 1H), 6.58 (s, 2H), 6.76 (d, 2H),6.9 (m, 1H), 7.09 (m, 2H), 7.15-7.3 (m, 4H), 13 (m, 2H).

BIOLOGICAL EXPERIMENTS

The compounds of formula I, which are subject matters of the presentinvention, and their therapeutically acceptable salts have advantageouspharmacological properties.

These derivatives are active in the cardiomyocyte by inhibition ofdiastolic contraction induced by veratrine in the rat isolated leftatrium. These compounds also reduce diastolic contraction during inducedischemia with respect to the guinea pig perfused isolated heart withoutaffecting the base hemodynamic properties, which makes them highlyselected products for ischemia.

These compounds are also active in vivo during ischemia-reperfusion inthe anesthetized rabbit: they inhibit electrical disturbances of the ECGbrought about by ischemia-reperfusion without a major hemodynamiceffect; they are not cardiac depressants.

The molecules of the present invention are of use preventively orcuratively in the treatment of coronaropathies, of all forms of anginaand of all forms of cardiac and cerebral ischemia and in the treatmentof atherosclerosis, cardiac insufficiency, epilepsy, pain and migraine.

1) Pharmacological study:

The experiments to which the chemical molecules which are a subjectmatter of the present invention have been subjected have made itpossible to demonstrate a promising activity with regard to thecardiovascular system, both by “in vitro” and “in vivo” tests.

a) “in vitro” action:

The inhibition of the contraction with veratrine of the rat isolatedleft atrium was carried out according to the technique of Le Grand etal. (Naunyn-Schmiedebergs Arch. Pharmacol., (1993) 348, p. 184-190). Theresults are shown in Table I below, where the percentages of theinhibition are given at a concentration of 10⁻⁷M.

TABLE I PF Compound Ex. 1 Ex. 3 Ex. 13 Ex. 21 R 56865* Control** % 28%32% 34% 31% 33% 25% contraction inhibition at 10⁻⁷M*N-(1-(4-(4-Fluorophenoxy)butyl)piperidin-4-yl)-N-methyl-2-benzothiazolamine,cited in Patent EP 0 184 257.**N-[1-[4-(3,4-Difluorophenoxy)butyl]piperidin-4-yl]-N-methyl-4H-3,1-benzothiazin-2-amine,disclosed in Patent WO 97/05134.

The antiischemic activity was measured with regard to the test of theguinea pig perfused isolated heart according to the technique of LeGrand B. et al. (Am. J. Physiol., 269, H533-H540, 1995). The guinea pighearts are removed, perfused with a modified Krebs solution and thecompound to be studied, in solution in water or in a 99/01 water/DMSOmixture (according to solubility), is added after 20 minutes. Afterminutes, global ischemia is brought about by halting coronary perfusionfor 50 min, followed by reperfusion for 1 h. The inhibition of ischemiccontraction in the presence of the compound studied is measured withrespect to that of the vehicle group. The results are shown in Table IIas nonlimiting examples at a concentration of 10⁻⁶M.

TABLE II Compound Example 1 Example 21 PF Control** % inhibition 69% 53%48 of the contraction at 10⁻⁶M **see Table I.

b) “in vivo” activity:

The compounds of the present invention are also active orally in thetest of ischemia-reperfusion in the anesthetized rabbit according to themethod of Verscheure et al., (J. Cardiovasc. Pharmacol., 1995, 25,126-133). The results for compound 1 are given as nonlimiting example inthe following Table III:

TABLE III No. of % inhibition Number of the with animals % Product Doseregard to exhibiting % heart arterial or mg/kg ST-segment reperfusionrate pressure Control p.o. elevation arrhythmias variation variation 10.63 58% 1/5 5 −3 PF 0.63 33% 1/5 9 9 Control** R 2.5   0% 2/5 0 2756865* * and **: see Table I

2) Therapeutic applications:

The compounds of the present invention and their therapeuticallyacceptable salts are of use as medicaments.

These compounds are more particularly suitable in cardiology in theprophylactic treatment of cardiovascular diseases, such as:

ischemia of the myocardium and coronaropathies and more particularly incrises:

of chronic stable angina,

of unstable and Prinzmetal's angina,

silent ischemia, and in the prevention of reocclusions, restenoses andreinfarction;

cerebral ischemia and more specifically in:

strokes,

transitory ischemic attack,

neurodegenerative diseases,

atherosclerosis,

cardiac insufficiency,

hypertension.

These compounds can also be used in the treatment of epilepsy, migraineand pain.

These compounds can be administered orally, parenterally or rectally.Each dose is composed of an inert adjuvant which promotes thepreparation and absorption of the medicament; it being possible for theactive principle also to be combined with another active principle.

These medicaments can be provided in the solid form (tablets or gelatincapsules) or liquid form to be prepared at the time of use (suspensions,emulsions, syrups, solutions or others) or in the form of suppositories.The active principle is administered at the mean dose of between 0.1 and10 mg/kg of the weight of the body.

Two preparations are given as nonlimiting examples. The ingredients andother therapeutically acceptable ingredients can be introduced in otherproportions without modifying the scope of the invention.

EXAMPLE 23 Injectable Solution

(to be prepared at the time of use)

1) A sterile bottle for injectable preparation made of inactinic glasshaving: 1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy) 10 mgbutyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate 2) A solventvial made of sterile glass having Propylene glycol 80 mg Anhydrousdextrose 40 mg Sterile distilled water, q.s. for  2 ml

EXAMPLE 24 Tablets

1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)  30 mgbutyl]piperidin-4-yl]-3-phenylisothiourea hydrogen fumarate Lactosehydrate  90 mg Microcrystalline cellulose  20 mg Magnesium stearate  5mg Maize starch  20 mg Talc  3 mg Polyvinylpyrrolidone  7 mg Totalweight 175 mg

What is claimed is:
 1. A substituted1,2-dialkyl-1-[1-(aryl(alkyl)oxyalkyl)-piperidin-4-yl]-3-arylisothioureaof formula I:

in which: R₁ and R₂, which are identical or different, represent asaturated or unsaturated, branched or unbranched, alkyl radical having 1to 7 carbon atoms, R₃ to R₈, which are identical or different,represent: a hydrogen, a branched or unbranched alkyl having 1 to 5carbon atoms, a branched or unbranched alkyloxy having 1 to 5 carbonatoms, a halo group, a nitro group, a hydroxyl group, an acyl or acyloxygroup comprising 1 to 5 carbon atoms, a dialkylamino group having 1 to 5carbon atoms, a trifluoromethyl or trifluoromethoxyl group, Z representsan oxygen or sulfur atom or a methylene, m represents an integer from 0to 4 inclusive, n represents an integer from 2 to 7 inclusive; with theproviso that at least one of R₃ to R₅ and one of R₆ to R₈ is hydrogen,its pure enantiomers, mixtures, and therapeutically acceptable organicor inorganic salts.
 2. A compound of claim 1 which is selected from thefollowing compounds:1,2-Dimethyl-3-phenyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]isothioureahydrogen fumarate;2-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-1-methyl-3-phenylisothioureahydrogen fumarate;1-Ethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothioureahydrogen fumarate;1-Isobutyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-2-methyl-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[5-(3,4-difluorophenoxy)pentyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[3-(3,4-difluorophenoxy)propyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(4-fluorophenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[2-(4-fluorophenoxy)ethyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(4-methoxyphenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-dimethylphenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(2-methoxy-4-chlorophenoxy)butyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2-fluorophenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-fluorophenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-chlorophenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methylphenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-methoxyphenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-dimethylphenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-[2,6-diisopropylphenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(3-fluorophenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(4-nitrophenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[4-(3,4-difluorophenoxy)butyl]piperidin-4-yl]-3-(2,6-difluorophenyl)isothioureahydrogen fumarate;1,2-Dimethyl-1-[1-[3-[2-(4-fluorophenyl)ethoxy]propyl]piperidin-4-yl]-3-phenylisothioureahydrogen fumarate.
 3. Process for the preparation of a chemical compoundof claim 1, wherein an isothiocyanate of formula (III):

is reacted with a diamine of formula (II):

in a protic solvent, such as ethanol, or an aprotic solvent, such as THFor dioxane, by heating or not heating at reflux, to give theintermediate thiourea of formula (IV):

which is subsequently S-alkylated with a halide R₁Br or R₁I or an alkylsulfate (R₁)₂S₄ in a protic solvent, such as alcohol, or an aproticsolvent, such as THF, DMF or ethyl acetate, with or without the presenceof lime at a temperature between 20 and 60° C., to give the compound Iof the present invention, it being understood that the formulae II, IIIand IV, the R₁ to R₈ and Z radicals and the numbers m and n have thesame values as in claim
 1. 4. A pharmaceutical composition whichcontains as active principle a compound of claim 1, combined with aninert pharmaceutical support, or other pharmaceutically-acceptablevehicles, which may be combined with another medicinal product.
 5. Amethod of treating a living body afflicted with a condition requiringthe prophylactic treatment of myocardial ischemia selected from chronicstable angina, unstable angina and Prinzmetal's angina attacks, silentischemia, reinfarction, reocclusion and restenosis, comprising the stepof administering an effective amount of a compound of claim 1 to apatient in need thereof.
 6. A method-of-treating atherosclerosis in aliving body comprising the step of administering an effective amount ofa compound of claim 1 to a patient in need thereof.
 7. Amethod-of-treating a living body afflicted with a condition selectedfrom cardiac insufficiency and hypertension comprising the step ofadministering an effective amount of a compound of claim 1 to a patientin need thereof.